The development of breast cancer is a consequence of genetic risks and environmental exposures. Polychlorinated biphenyls (PCBs) are environmental contaminants that, despite their banned use, represent ongoing threats to humans due to their persistence in lipid-rich tissues, such as breast. To dissect PCB gene- environment interactions, it is necessary to gain an understanding of the mechanisms by which PCBs can act to enhance breast carcinogenesis. PCBs are chemically and toxicologically diverse molecules, as planar PCBs activate the aryl hydrocarbon receptor, while non-planar PCBs activate alternative xenobiotic-sensing receptors. Many PCB congeners are capable of exerting estrogenic effects and/or inducing oxidative stress. Certain PCBs are biotransformed to hydroxylated metabolites, which can further propagate oxidative stress and/or estrogenic effects. For example, while some hydroxylated PCBs are estrogen receptor (ER) ligands, others are potent inhibitors of estrogen sulfotransferase, the major estrogen-inactivating enzyme in human breast epithelial cells. The effects of PCB treatments have never been evaluated in an in vivo model of human breast cancer progression. The MCF10AT1 xenograft model, in which subcutaneously implanted preneoplastic human breast epithelial cells form lesions that progressively advance toward neoplasia, provides a unique opportunity to dissect the mechanisms by which PCBs affect human breast cancer progression in vivo. The hypothesis of this proposal is that PCBs of different classes accelerate the progression of pre-malignant breast epithelial cells to persistent lesions that represent more advanced stages of malignant transformation. The effects of different classes of PCBs on xenograft progression reflect their relative abilities to (1) exert pro- estrogenic effects and (2) induce oxidative stress. Specific aim 1 will define the effects of treatments with PCBs that are prototypes of (1) the planar PCBs, (2) the non-planar PCBs and (3) hydroxylated PCB metabolites on human breast tumorigenesis in the MCF10AT1 xenograft model. Specific aim 2 will determine whether PCB- mediated effects on human breast tumorigenesis are mediated through (1) ER-dependent, (2) oxidative stress- dependent and/or (3) cytochrome P450 metabolism-dependent mechanisms. These studies will shed new light on the core mechanisms by which PCBs shift breast tissue homeostasis toward advancing neoplasia. The development of breast cancer is a consequence of genetic risks and environmental exposures. Polychlorinated biphenyls (PCBs) are environmental contaminants that, despite their banned use, represent ongoing threats to humans due to their persistence in lipid-rich tissues, such as breast. However, the effects of PCBs have never been evaluated in an in vivo model of human breast cancer progression. These studies will employ a unique model of human breast cancer progression to shed new light on the core mechanisms by which environmental PCBs promote cancer development.